The human thyrotropin (TSH) beta subunit gene has been isolated and sequenced. It differs from previously isolated rodent TSH-beta genes in promotor organization, which may have important implications for promotor function in man. The gene has been expressed in mammalian cells, and by co-transfection with excess alpha subunit cDNA, biologically active thyrotropin has been produced. Currently we are studying regulatory elements in the promotor region of the gene to understand the control of TSH production in man. Similarly, through site directed mutagenesis we are exploring structure-function relationships of the coding regions of the gene. Hypothalamic regulation of TSH is being studied by examining TRH messenger RNA in rodents of various ages and different endocrine status. We have observed that hypothalamic factors are important in the pituitary response to hypothyroidism. The syndrome of generalized thyroid hormone resistance has been linked to the human c-erbA beta gene by restriction fragment length polymorphism analysis. This implies that the beta gene codes for a receptor important for thyroid hormone action in man.